title: Identification of a receptor for neuropeptide VGF and its role in neuropathic pain.
abstract: VGF (nonacronymic) is a neuropeptide precursor that plays multiple roles in regulation of energy balance, reproduction, hippocampal synaptic plasticity, and pain. Data from a number of pain models showed significant up-regulation of VGF in sensory neurons. TLQP-21, one of the VGF-derived neuropeptides, has been shown to induce a hyperalgesic response when injected subcutaneously into the hind paw of mice. However, the precise role of VGF-derived neuropeptides in neuropathic pain and the molecular identity of the receptor for VGF-derived peptides are yet to be investigated. Here we identified gC1qR, the globular heads of the C1q receptor, as the receptor for TLQP-21 using chemical cross-linking combined with mass spectrometry analysis. TLQP-21 caused an increase in intracellular Ca(2+) levels in rat macrophages and microglia. Inoculation of TLQP-21-stimulated macrophages into rat hind paw caused mechanical hypersensitivity. The increase in intracellular Ca(2+) levels in macrophages was attenuated by either siRNA or neutralizing antibodies against gC1qR. Furthermore, application of the gC1qR-neutralizing antibody to rats with partial sciatic nerve ligation resulted in a delayed onset of nerve injury-associated mechanical hypersensitivity. These results indicate that gC1qR is the receptor for TLQP-21 and plays an important role in chronic pain through activation of macrophages. Because direct association between TLQP-21 and gC1qR is required for activation of macrophages and causes hypersensitivity, disrupting this interaction may be a useful new approach to develop novel analgesics.
authors.affiliation: From the Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom and.
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pristerá
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ayub
authors.forename: Richard S
authors.initials: RS
authors.lastname: Swanwick
authors.forename: Kersti
authors.initials: K
authors.lastname: Karu
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hamada
authors.forename: Andrew S C
authors.initials: AS
authors.lastname: Rice
authors.forename: Kenji
authors.initials: K
authors.lastname: Okuse
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D011951:Receptors, Complement / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D009479:Neuropeptides; D010446:Peptide Fragments; D011951:Receptors, Complement; D018013:Receptors, Neuropeptide; C522412:TLQP-21 peptide; C522413:VGF peptide; C032402:complement 1q receptor; D002118:Calcium
keywords: Calcium Intracellular Release; Macrophages; Neurons; Neuropathic Pain; Neuropeptide; Pain; Sensory Neurons; VGF; gC1qR